YAP Partially Reprograms Chromatin Accessibility to Directly Induce Adult Cardiogenesis In Vivo

Dev Cell. 2019 Mar 25;48(6):765-779.e7. doi: 10.1016/j.devcel.2019.01.017. Epub 2019 Feb 14.


Specialized adult somatic cells, such as cardiomyocytes (CMs), are highly differentiated with poor renewal capacity, an integral reason underlying organ failure in disease and aging. Among the least renewable cells in the human body, CMs renew approximately 1% annually. Consistent with poor CM turnover, heart failure is the leading cause of death. Here, we show that an active version of the Hippo pathway effector YAP, termed YAP5SA, partially reprograms adult mouse CMs to a more fetal and proliferative state. One week after induction, 19% of CMs that enter S-phase do so twice, CM number increases by 40%, and YAP5SA lineage CMs couple to pre-existing CMs. Genomic studies showed that YAP5SA increases chromatin accessibility and expression of fetal genes, partially reprogramming long-lived somatic cells in vivo to a primitive, fetal-like, and proliferative state.

Keywords: Hippo pathway; Yap; cardiomyocyte proliferation; chromatin accessibility; heart development; heart failure; regeneration; reprogramming; transcription.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Aging / physiology*
  • Animals
  • Cardiomegaly / pathology
  • Cardiomegaly / physiopathology
  • Cell Cycle
  • Cell Cycle Proteins
  • Cell Lineage
  • Cell Proliferation
  • Chromatin / metabolism*
  • Diploidy
  • Enhancer Elements, Genetic / genetics
  • Gain of Function Mutation / genetics
  • Gene Expression Regulation, Developmental
  • Heart / growth & development*
  • Heart Ventricles / anatomy & histology
  • Mice, Transgenic
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism
  • Organogenesis* / genetics
  • Phosphoproteins / metabolism*
  • Promoter Regions, Genetic / genetics
  • Transcription Factor AP-1 / metabolism
  • Transgenes
  • YAP-Signaling Proteins


  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Chromatin
  • Phosphoproteins
  • Transcription Factor AP-1
  • YAP-Signaling Proteins
  • Yap1 protein, mouse